Artificial intelligence and classification of mature lymphoid neoplasms.

Hematologists, geneticists, and clinicians came to a multidisciplinary agreement on the classification of lymphoid neoplasms that combines clinical features, histological characteristics, immunophenotype, and molecular pathology analyses. The current classification includes the World Health Organization (WHO) Classification of tumours of haematopoietic and lymphoid tissues revised 4th edition, the International Consensus Classification (ICC) of mature lymphoid neoplasms (report from the Clinical Advisory Committee 2022), and the 5th edition of the proposed WHO Classification of haematolymphoid tumours (lymphoid neoplasms, WHO-HAEM5). This article revises the recent advances in the classification of mature lymphoid neoplasms. Artificial intelligence (AI) has advanced rapidly recently, and its role in medicine is becoming more important as AI integrates computer science and datasets to make predictions or classifications based on complex input data. Summarizing previous research, it is described how several machine learning and neural networks can predict the prognosis of the patients, and classified mature B-cell neoplasms. In addition, new analysis predicted lymphoma subtypes using cell-of-origin markers that hematopathologists use in the clinical routine, including CD3, CD5, CD19, CD79A, MS4A1 (CD20), MME (CD10), BCL6, IRF4 (MUM-1), BCL2, SOX11, MNDA, and FCRL4 (IRTA1). In conclusion, although most categories are similar in both classifications, there are also conceptual differences and differences in the diagnostic criteria for some diseases. It is expected that AI will be incorporated into the lymphoma classification as another bioinformatics tool.

Epigenetic alterations in creatine transporter deficiency: a new marker for dodecyl creatine ester therapeutic efficacy monitoring.

Creatine transporter deficiency (CTD) is an X-linked disease caused by mutations in the Slc6a8 gene. The impaired creatine uptake in the brain leads to developmental delays with intellectual disability. We hypothesized that deficient creatine uptake in CTD cerebral cells impact methylation balance leading to alterations of genes and proteins expression by epigenetic mechanism. In this study, we determined the status of nucleic acid methylation in both Slc6a8 knockout mouse model and brain organoids derived from CTD patients' cells. We also investigated the effect of dodecyl creatine ester (DCE), a promising prodrug that increases brain creatine content in the mouse model of CTD. The level of nucleic acid methylation was significantly reduced compared to healthy controls in both in vivo and in vitro CTD models. This hypo-methylation tended to be regulated by DCE treatment in vivo. These results suggest that increased brain creatine after DCE treatment restores normal levels of DNA methylation, unveiling the potential of using DNA methylation as a marker to monitor the drug efficacy.

Unlocking the Therapeutic Potential of BCL-2 Associated Protein Family: Exploring BCL-2 Inhibitors in Cancer Therapy.

Apoptosis, programmed cell death pathway, is a vital physiological mechanism that ensures cellular homeostasis and overall cellular well-being. In the context of cancer, where evasion of apoptosis is a hallmark, the overexpression of anti-apoptotic proteins like Bcl2, Bcl-xL and Mcl-1 has been documented. Consequently, these proteins have emerged as promising targets for therapeutic interventions. The BCL-2 protein family is central to apoptosis and plays a significant importance in determining cellular fate serving as a critical determinant in this biological process. This review offers a comprehensive exploration of the BCL-2 protein family, emphasizing its dual nature. Specifically, certain members of this family promote cell survival (known as anti-apoptotic proteins), while others are involved in facilitating cell death (referred to as pro-apoptotic and BH3-only proteins). The potential of directly targeting these proteins is examined, particularly due to their involvement in conferring resistance to traditional cancer therapies. The effectiveness of such targeting strategies is also discussed, considering the tumor's propensity for anti-apoptotic pathways. Furthermore, the review highlights emerging research on combination therapies, where BCL-2 inhibitors are used synergistically with other treatments to enhance therapeutic outcomes. By understanding and manipulating the BCL-2 family and its associated pathways, we open doors to innovative and more effective cancer treatments, offering hope for resistant and aggressive cases.

The role of RNA-modifying proteins in renal cell carcinoma.

Gene expression is one of the most critical cellular processes. It is controlled by complex mechanisms at the genomic, epigenomic, transcriptomic, and proteomic levels. Any aberration in these mechanisms can lead to dysregulated gene expression. One recently discovered process that controls gene expression includes chemical modifications of RNA molecules by RNA-modifying proteins, a field known as epitranscriptomics. Epitranscriptomics can regulate mRNA splicing, nuclear export, stabilization, translation, or induce degradation of target RNA molecules. Dysregulation in RNA-modifying proteins has been found to contribute to many pathological conditions, such as cancer, diabetes, obesity, cardiovascular diseases, and neurological diseases, among others. This article reviews the role of epitranscriptomics in the pathogenesis and progression of renal cell carcinoma. It summarizes the molecular function of RNA-modifying proteins in the pathogenesis of renal cell carcinoma.

Mutational, immune microenvironment, and clinicopathological profiles of diffuse large B-cell lymphoma and follicular lymphoma with BCL6 rearrangement.

BCL6-rearrangement (BCL6-R) is associated with a favorable prognosis of follicular lymphoma (FL), but the mechanism is unknown. We analyzed the clinicopathological, immune microenvironment (immune checkpoint, immuno-oncology markers), and mutational profiles of 10 BCL6-R-positive FL, and 19 BCL6-R-positive diffuse large B-cell lymphoma (DLBCL) cases (both BCL2-R and MYC-R negative). A custom-made panel included 168 genes related to aggressive B-cell lymphomas and FL. FL cases were nodal, histological grade 3A in 70%, low Ki67; and had a favorable overall and progression-free survival. DLBCL cases were extranodal in 60%, IPI high in 63%, non-GCB in 60%, EBER-negative; and had a progression-free survival comparable to that of DLBCL NOS. The microenvironment had variable infiltration of M2-like tumor-associated macrophages (TAMs) that were CD163, CSF1R, LAIR1, PD-L1, and CD85A (LILRB3) positive; but had low IL10 and PTX3 expression. In comparison to FL, DLBCL had higher TAMs, IL10, and PTX3 expression. Both lymphoma subtypes shared a common mutational profile with mutations in relevant pathogenic genes such as KMT2D, OSBPL10, CREBBP, and HLA-B (related to chromatin remodeling, metabolism, epigenetic modification, and antigen presentation). FL cases were characterized by a higher frequency of mutations of ARID1B, ATM, CD36, RHOA, PLOD2, and PRPRD (p < 0.05). DLBCL cases were characterized by mutations of BTG2, and PIM1; and mutations of HIST1H1E and MFHAS1 to disease progression (p < 0.05). Interestingly, mutations of genes usually associated with poor prognosis, such as NOTCH1/2 and CDKN2A, were infrequent in both lymphoma subtypes. Some high-confidence variant calls were likely oncogenic, loss-of-function. MYD88 L265P gain-of-function was found in 32% of DLBCL. In conclusion, both BCL6-R-positive FL and BCL6-R-positive DLBCL had a common mutational profile; but also, differences. DLBCL cases had a higher density of microenvironment markers.

Potential of CDC25 phosphatases in cancer research and treatment: key to precision medicine.

The global burden of cancer continues to rise, underscoring the urgency of developing more effective and precisely targeted therapies. This comprehensive review explores the confluence of precision medicine and CDC25 phosphatases in the context of cancer research. Precision medicine, alternatively referred to as customized medicine, aims to customize medical interventions by taking into account the genetic, genomic, and epigenetic characteristics of individual patients. The identification of particular genetic and molecular drivers driving cancer helps both diagnostic accuracy and treatment selection. Precision medicine utilizes sophisticated technology such as genome sequencing and bioinformatics to elucidate genetic differences that underlie the proliferation of cancer cells, hence facilitating the development of customized therapeutic interventions. CDC25 phosphatases, which play a crucial role in governing the progression of the cell cycle, have garnered significant attention as potential targets for cancer treatment. The dysregulation of CDC25 is a characteristic feature observed in various types of malignancies, hence classifying them as proto-oncogenes. The proteins in question, which operate as phosphatases, play a role in the activation of Cyclin-dependent kinases (CDKs), so promoting the advancement of the cell cycle. CDC25 inhibitors demonstrate potential as therapeutic drugs for cancer treatment by specifically blocking the activity of CDKs and modulating the cell cycle in malignant cells. In brief, precision medicine presents a potentially fruitful option for augmenting cancer research, diagnosis, and treatment, with an emphasis on individualized care predicated upon patients' genetic and molecular profiles. The review highlights the significance of CDC25 phosphatases in the advancement of cancer and identifies them as promising candidates for therapeutic intervention. This statement underscores the significance of doing thorough molecular profiling in order to uncover the complex molecular characteristics of cancer cells.

Design, synthesis and mechanistic anticancer activity of new acetylated 5-aminosalicylate-thiazolinone hybrid derivatives.

The development of hybrid compounds has been widely considered as a promising strategy to circumvent the difficulties that emerge in cancer treatment. The well-established strategy of adding acetyl groups to certain drugs has been demonstrated to enhance their therapeutic efficacy. Based on our previous work, an approach of accommodating two chemical entities into a single structure was implemented to synthesize new acetylated hybrids (HH32 and HH33) from 5-aminosalicylic acid and 4-thiazolinone derivatives. These acetylated hybrids showed potential anticancer activities and distinct metabolomic profile with antiproliferative properties. The in-silico molecular docking predicts a strong binding of HH32 and HH33 to cell cycle regulators, and transcriptomic analysis revealed DNA repair and cell cycle as the main targets of HH33 compounds. These findings were validated using in vitro models. In conclusion, the pleiotropic biological effects of HH32 and HH33 compounds on cancer cells demonstrated a new avenue to develop more potent cancer therapies.

Combination of verteporfin-photodynamic therapy with 5-aza-2'-deoxycytidine enhances the anti-tumour immune response in triple negative breast cancer.

Introduction: Triple negative breast cancer (TNBC) is a subtype of breast cancer characterised by its high tumourigenic, invasive, and immunosuppressive nature. Photodynamic therapy (PDT) is a focal therapy that uses light to activate a photosensitizing agent and induce a cytotoxic effect. 5-aza-2'-deoxycytidine (5-ADC) is a clinically approved immunomodulatory chemotherapy agent. The mechanism of the combination therapy using PDT and 5-ADC in evoking an anti-tumour response is not fully understood. Methods: The present study examined whether a single dose of 5-ADC enhances the cytotoxic and anti-tumour immune effect of low dose PDT with verteporfin as the photosensitiser in a TNBC orthotopic syngeneic murine model, using the triple negative murine mammary tumour cell line 4T1. Histopathology analysis, digital pathology and immunohistochemistry of treated tumours and distant sites were assessed. Flow cytometry of splenic and breast tissue was used to identify T cell populations. Bioinformatics were used to identify tumour immune microenvironments related to TNBC patients. Results: Functional experiments showed that PDT was most effective when used in combination with 5-ADC to optimize its efficacy. 5-ADC/PDT combination therapy elicited a synergistic effect in vitro and was significantly more cytotoxic than monotherapies on 4T1 tumour cells. For tumour therapy, all types of treatments demonstrated histopathologically defined margins of necrosis, increased T cell expression in the spleen with absence of metastases or distant tissue destruction. Flow cytometry and digital pathology results showed significant increases in CD8 expressing cells with all treatments, whereas only the 5-ADC/PDT combination therapy showed increase in CD4 expression. Bioinformatics analysis of in silico publicly available TNBC data identified BCL3 and BCL2 as well as the following anti-tumour immune response biomarkers as significantly altered in TNBC compared to other breast cancer subtypes: GZMA, PRF1, CXCL1, CCL2, CCL4, and CCL5. Interestingly, molecular biomarker assays showed increase in anti-tumour response genes after treatment. The results showed concomitant increase in BCL3, with decrease in BCL2 expression in TNBC treatment. In addition, the treatments showed decrease in PRF1, CCL2, CCL4, and CCL5 genes with 5-ADC and 5-ADC/PDT treatment in both spleen and breast tissue, with the latter showing the most decrease. Discussion: To our knowledge, this is the first study that shows which of the innate and adaptive immune biomarkers are activated during PDT related treatment of the TNBC 4T1 mouse models. The results also indicate that some of the immune response biomarkers can be used to monitor the effectiveness of PDT treatment in TNBC murine model warranting further investigation in human subjects.

Unveiling the molecular Culprit of arterial stiffness in vitamin D deficiency and obesity: Potential for novel therapeutic targets.

Cardiovascular diseases (CVDs) are highly associated with both vitamin D deficiency and obesity, two prevalent health conditions worldwide. Arterial stiffness, an independent predictor of CVDs, is particularly elevated in both conditions, yet the molecular mechanisms underlying this phenomenon remain elusive, hindering effective management of CVDs in this population. We recruited 20 middle-aged Emiratis, including 9 individuals with vitamin D deficiency (Vit D level ≤20 ng) and obesity (BMI ≥30) and 11 individuals as control with Vit D level >20 ng and BMI <30. We measured arterial stiffness using pulse wave velocity (PWV) and performed whole transcriptome sequencing to identify differentially expressed genes (DEGs) and enriched pathways. We validated these findings using qRT-PCR, Western blot, and multiplex analysis. PWV was significantly higher in the vitamin D deficient and obese group relative to controls (p ≤ 0.05). The DEG analysis revealed that pathways related to interleukin 1 (IL-1), nitrogen metabolism, HIF-1 signaling, and MAPK signaling were over-activated in the vitamin D deficient and obese group. We found that HIF-1alpha, NOX-I, NOX-II, IL-1b, IL-8, IL-10, and VEGF were significantly upregulated in the vitamin D deficient and obese group (p < 0.05). Our study provides new insights into the molecular mechanisms of arterial stiffness in vitamin D deficiency and obesity, demonstrating the role of oxidative stress and inflammation in this process. Our findings suggest that these biomarkers may serve as potential therapeutic targets for early prevention of CVDs. Further studies are needed to investigate these pathways and biomarkers with larger cohort.

Exosomes Interactions with the Blood-Brain Barrier: Implications for Cerebral Disorders and Therapeutics.

The Blood-Brain Barrier (BBB) is a selective structural and functional barrier between the circulatory system and the cerebral environment, playing an essential role in maintaining cerebral homeostasis by limiting the passage of harmful molecules. Exosomes, nanovesicles secreted by virtually all cell types into body fluids, have emerged as a major mediator of intercellular communication. Notably, these vesicles can cross the BBB and regulate its physiological functions. However, the precise molecular mechanisms by which exosomes regulate the BBB remain unclear. Recent research studies focused on the effect of exosomes on the BBB, particularly in the context of their involvement in the onset and progression of various cerebral disorders, including solid and metastatic brain tumors, stroke, neurodegenerative, and neuroinflammatory diseases. This review focuses on discussing and summarizing the current knowledge about the role of exosomes in the physiological and pathological modulation of the BBB. A better understanding of this regulation will improve our understanding of the pathogenesis of cerebral diseases and will enable the design of effective treatment strategies.

Brain organoids for hypoxic-ischemic studies: from bench to bedside.

Our current knowledge regarding the development of the human brain mostly derives from experimental studies on non-human primates, sheep, and rodents. However, these studies may not completely simulate all the features of human brain development as a result of species differences and variations in pre- and postnatal brain maturation. Therefore, it is important to supplement the in vivo animal models to increase the possibility that preclinical studies have appropriate relevance for potential future human trials. Three-dimensional brain organoid culture technology could complement in vivo animal studies to enhance the translatability of the preclinical animal studies and the understanding of brain-related disorders. In this review, we focus on the development of a model of hypoxic-ischemic (HI) brain injury using human brain organoids to complement the translation from animal experiments to human pathophysiology. We also discuss how the development of these tools provides potential opportunities to study fundamental aspects of the pathophysiology of HI-related brain injury including differences in the responses between males and females.

Reappraisal of the Concept of Accelerated Aging in Neurodegeneration and Beyond.

BACKGROUND: Genetic and epigenetic changes, oxidative stress and inflammation influence the rate of aging, which diseases, lifestyle and environmental factors can further accelerate. In accelerated aging (AA), the biological age exceeds the chronological age. OBJECTIVE: The objective of this study is to reappraise the AA concept critically, considering its weaknesses and limitations. METHODS: We reviewed more than 300 recent articles dealing with the physiology of brain aging and neurodegeneration pathophysiology. RESULTS: (1) Application of the AA concept to individual organs outside the brain is challenging as organs of different systems age at different rates. (2) There is a need to consider the deceleration of aging due to the potential use of the individual structure-functional reserves. The latter can be restored by pharmacological and/or cognitive therapy, environment, etc. (3) The AA concept lacks both standardised terminology and methodology. (4) Changes in specific molecular biomarkers (MBM) reflect aging-related processes; however, numerous MBM candidates should be validated to consolidate the AA theory. (5) The exact nature of many potential causal factors, biological outcomes and interactions between the former and the latter remain largely unclear. CONCLUSIONS: Although AA is commonly recognised as a perspective theory, it still suffers from a number of gaps and limitations that assume the necessity for an updated AA concept.

Deciphering neuronal deficit and protein profile changes in human brain organoids from patients with creatine transporter deficiency.

Creatine transporter deficiency (CTD) is an X-linked disease caused by mutations in the SLC6A8 gene. The impaired creatine uptake in the brain results in intellectual disability, behavioral disorders, language delay, and seizures. In this work, we generated human brain organoids from induced pluripotent stem cells of healthy subjects and CTD patients. Brain organoids from CTD donors had reduced creatine uptake compared with those from healthy donors. The expression of neural progenitor cell markers SOX2 and PAX6 was reduced in CTD-derived organoids, while GSK3ß, a key regulator of neurogenesis, was up-regulated. Shotgun proteomics combined with integrative bioinformatic and statistical analysis identified changes in the abundance of proteins associated with intellectual disability, epilepsy, and autism. Re-establishment of the expression of a functional SLC6A8 in CTD-derived organoids restored creatine uptake and normalized the expression of SOX2, GSK3ß, and other key proteins associated with clinical features of CTD patients. Our brain organoid model opens new avenues for further characterizing the CTD pathophysiology and supports the concept that reinstating creatine levels in patients with CTD could result in therapeutic efficacy.

Integrative bioinformatics and artificial intelligence analyses of transcriptomics data identified genes associated with major depressive disorders including NRG1.

Major depressive disorder (MDD) is a common mental disorder and is amongst the most prevalent psychiatric disorders. MDD remains challenging to diagnose and predict its onset due to its heterogeneous phenotype and complex etiology. Hence, early detection using diagnostic biomarkers is critical for rapid intervention. In this study, a mixture of AI and bioinformatics were used to mine transcriptomic data from publicly available datasets including 170 MDD patients and 121 healthy controls. Bioinformatics analysis using gene set enrichment analysis (GSEA) and machine learning (ML) algorithms were applied. The GSEA revealed that differentially expressed genes in MDD patients are mainly enriched in pathways related to immune response, inflammatory response, neurodegeneration pathways and cerebellar atrophy pathways. Feature selection methods and ML provided predicted models based on MDD-altered genes with ≥75% of accuracy. The integrative analysis between the bioinformatics and ML approaches identified ten key MDD-related biomarkers including NRG1, CEACAM8, CLEC12B, DEFA4, HP, LCN2, OLFM4, SERPING1, TCN1 and THBS1. Among them, NRG1, active in synaptic plasticity and neurotransmission, was the most robust and reliable to distinguish between MDD patients and healthy controls amongst independent external datasets consisting of a mixture of populations. Further evaluation using saliva samples from an independent cohort of MDD and healthy individuals confirmed the upregulation of NRG1 in patients with MDD compared to healthy controls. Functional mapping to the human brain regions showed NRG1 to have high expression in the main subcortical limbic brain regions implicated in depression. In conclusion, integrative bioinformatics and ML approaches identified putative non-invasive diagnostic MDD-related biomarkers panel for the onset of depression.

Azithromycin downregulates ICOS (CD278) and OX40 (CD134) expression and mTOR activity of TCR-activated T cells to inhibit proliferation.

The precise mechanism of macrolide antibiotic azithromycin (AZM) mediated CD4+ T cell suppression is not fully understood. Given the crucial role of co-stimulatory signaling in T-lymphocyte function, we tested in vitro effects of AZM on two of the most extensively investigated costimulatory molecules, ICOS and OX40 in context to CD4+ T cell proliferation. Using multi-color flow cytometry approach on TCR-activated healthy donor peripheral blood mononuclear cells, we observed a marked reduction in the frequencies and surface expression of ICOS and OX40 receptors following AZM treatment. Functionally, in contrast to ICOS- and OX40- CD3+ CD4+ T cells, AZM treated ICOS+ and OX40+ displayed profound reduction in cell proliferation. Furthermore, AZM treated T cells displaying reduced levels of ICOS and OX40 found to be associated with suppressed mTOR activity as detected by phosphorylation levels of S6 ribosomal protein. This study provides new insights on potential mechanism of AZM mediated inhibition of T cell proliferation by targeting costimulatory pathways.

Molecular pathogenicity of 1-nonadecene and L-lactic acid, unique metabolites in radicular cysts and periapical granulomas.

Recently, 1-nonadecene and L-lactic acid were identified as unique metabolites in radicular cysts and periapical granuloma, respectively. However, the biological roles of these metabolites were unknown. Therefore, we aimed to investigate the inflammatory and mesenchymal-epithelial transition (MET) effects of 1-nonadecene, and the inflammatory and collagen precipitation effects of L-lactic acid on both periodontal ligament fibroblasts (PdLFs) and peripheral blood mononuclear cells (PBMCs). PdLFs and PBMCs were treated with 1-nonadecene and L-lactic acid. Cytokines' expression was measured using quantitative real-time polymerase chain reaction (qRT-PCR). E-cadherin, N-cadherin, and macrophage polarization markers were measured using flow cytometry. The collagen, matrix metalloproteinase (MMP)-1, and released cytokines were measured using collagen assay, western blot, and Luminex assay, respectively. In PdLFs, 1-nonadecene enhances inflammation through the upregulation of some inflammatory cytokines including IL-1ß, IL-6, IL-12A, monocyte chemoattractant protein (MCP)-1, and platelet-derived growth factor (PDGF) α. 1-Nonadecene also induced MET through the upregulation of E-cadherin and the downregulation of N-cadherin in PdLFs. 1-Nonadecene polarized macrophages to a pro-inflammatory phenotype and suppressed their cytokines' release. L-lactic acid exerted a differential impact on the inflammation and proliferation markers. Intriguingly, L-lactic acid induced fibrosis-like effects by enhancing collagen synthesis, while inhibiting MMP-1 release in PdLFs. These results provide a deeper understanding of 1-nonadecene and L-lactic acid's roles in modulating the microenvironment of the periapical area. Consequently, further clinical investigation can be employed for target therapy.

Titanium Particles Modulate Lymphocyte and Macrophage Polarization in Peri-Implant Gingival Tissues.

Titanium dental implants are one of the modalities to replace missing teeth. The release of titanium particles from the implant's surface may modulate the immune cells, resulting in implant failure. However, little is known about the immune microenvironment that plays a role in peri-implant inflammation as a consequence of titanium particles. In this study, the peri-implant gingival tissues were collected from patients with failed implants, successful implants and no implants, and then a whole transcriptome analysis was performed. The gene set enrichment analysis confirmed that macrophage M1/M2 polarization and lymphocyte proliferation were differentially expressed between the study groups. The functional clustering and pathway analysis of the differentially expressed genes between the failed implants and successful implants versus no implants revealed that the immune response pathways were the most common in both comparisons, implying the critical role of infiltrating immune cells in the peri-implant tissues. The H&E and IHC staining confirmed the presence of titanium particles and immune cells in the tissue samples, with an increase in the infiltration of lymphocytes and macrophages in the failed implant samples. The in vitro validation showed a significant increase in the level of IL-1ß, IL-8 and IL-18 expression by macrophages. Our findings showed evidence that titanium particles modulate lymphocyte and macrophage polarization in peri-implant gingival tissues, which can help in the understanding of the imbalance in osteoblast-osteoclast activity and failure of dental implant osseointegration.

The Role of Vitamin D Supplementation on Airway Remodeling in Asthma: A Systematic Review.

Asthma is a common chronic respiratory disease that affects millions of people worldwide, and its prevalence continues to increase. Vitamin D has been proposed as a potential environmental factor in asthma pathogenesis, due to its immunomodulatory effects. This systematic review aimed to evaluate the effect of vitamin D supplementation in order to prevent airway remodeling in asthmatic patients. Four electronic databases, namely PubMed, Embase, Clinical trails.gov, and CINAHL, were thoroughly searched to conduct a comprehensive literature review. The International Prospective Register of Systematic Reviews (CRD42023413798) contains a record of the registered protocol. We identified 9447 studies during the initial search; 9 studies (0.1%) met the inclusion criteria and were included in the systematic review. All included studies were experimental studies that investigated the impact of vitamin D supplementation on airway remodeling in asthma. The studies included in this review suggest that vitamin D inhibits airway smooth muscle cell contraction and remodeling, reduces inflammation, regulates collagen synthesis in the airways, and modulates the action of bronchial fibroblasts. However, one study suggests that TGF-ß1 can impair vitamin D-induced and constitutive airway epithelial host defense mechanisms. Overall, vitamin D appears to have a potential role in the prevention and management of asthma.

Insights into the Molecular Mechanisms Mediating Extravasation in Brain Metastasis of Breast Cancer, Melanoma, and Lung Cancer.

Brain metastasis is an incurable end-stage of systemic cancer associated with poor prognosis, and its incidence is increasing. Brain metastasis occurs through a multi-step cascade where cancer cells spread from the primary tumor site to the brain. The extravasation of tumor cells through the blood-brain barrier (BBB) is a critical step in brain metastasis. During extravasation, circulating cancer cells roll along the brain endothelium (BE), adhere to it, then induce alterations in the endothelial barrier to transmigrate through the BBB and enter the brain. Rolling and adhesion are generally mediated by selectins and adhesion molecules induced by inflammatory mediators, while alterations in the endothelial barrier are mediated by proteolytic enzymes, including matrix metalloproteinase, and the transmigration step mediated by factors, including chemokines. However, the molecular mechanisms mediating extravasation are not yet fully understood. A better understanding of these mechanisms is essential as it may serve as the basis for the development of therapeutic strategies for the prevention or treatment of brain metastases. In this review, we summarize the molecular events that occur during the extravasation of cancer cells through the blood-brain barrier in three types of cancer most likely to develop brain metastasis: breast cancer, melanoma, and lung cancer. Common molecular mechanisms driving extravasation in these different tumors are discussed.